WO2023076930A1 - Methods of treating head and neck cancers with hemp extract - Google Patents
Methods of treating head and neck cancers with hemp extract Download PDFInfo
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- WO2023076930A1 WO2023076930A1 PCT/US2022/078693 US2022078693W WO2023076930A1 WO 2023076930 A1 WO2023076930 A1 WO 2023076930A1 US 2022078693 W US2022078693 W US 2022078693W WO 2023076930 A1 WO2023076930 A1 WO 2023076930A1
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- cbd
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- cannabis extract
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the inventions disclosed herein are related to methods of use of cannabis extracts and treatment methods using cannabis extracts comprising CBD for treatment of head and neck cancers through oral, oral mucosal, rectal, and intravaginal applications.
- the cannabis extracts comprise one or more cannabinoids, and specifically therapeutic amounts of cannabidiol (CBD) and often include one or more additional cannabinoid, terpene, or other molecules within the cannabis extract.
- CBD cannabidiol
- Cancer represents the phenotypic end-point of multiple genetic lesions that endow cells with a full range of biological properties required for tumorigenesis.
- a hallmark genomic feature of many cancers including, for example, head and neck cancer, is the presence of numerous complex chromosome structural aberrations, including translocations, intra- chromosomal inversions, point mutations, deletions, gene copy number changes, gene expression level changes, and germline mutations, among others. Whether a cancer will respond to a particular treatment option may depend on the particular genomic features present in the cancer.
- Head and neck cancers are those which develop from tissues in the lip and oral cavity, larynx, esophagus, salivary glands, nose, sinuses, or the skin of the face.
- the majority of head and neck cancer is caused by the use of alcohol or tobacco, with increasing cases linked to human papillomavirus (HPV).
- HPV human papillomavirus
- other factors may include Epstein-Barr virus, radiation exposure, and certain workplace exposures.
- the majority of cancers, roughly 90%, are pathologically classified as squamous cell cancers, which can be diagnosed and confirmed by tissue biopsy.
- head and neck cancers account for more than 650,000 new cases a year with at least 330,000 annual deaths. In the United States, head and neck cancers account for 3% of all cancer cases, and 1.5% of cancer deaths. The average age of diagnosis is approximately 60 years old and the five-year survival in the developed world is roughly 50%.
- Treatment for head and neck cancers typically begin with resection of any known tumor cells. However, this can be particularly difficult when the cancer is on or adjacent to the larynx, which may damage the vocal cords or render the patient unable to speak. Other surgical procedures are also difficult, as they can be significantly deforming to the face, leading to secondary issues with well-being, even with successful treatment. Surgery is often used to remove the cervical lymph nodes to prevent spread of disease. After surgery, patients typically undergo radiation therapy, such as 3D conformal radiation therapy, intensity-modulated radiation therapy, particle beam therapy and brachytherapy. Chemotherapies are then frequently used to prevent or control metastases of the cancer within the body. Typically, these include some form of paclitaxel and carboplatin. However, the response to one treatment may be highly individualized and thus certain cancer treatment are effective for one and ineffective for another.
- radiation therapy such as 3D conformal radiation therapy, intensity-modulated radiation therapy, particle beam therapy and brachytherapy.
- Chemotherapies are then frequently used to prevent or control metastases of
- Preferred embodiments are directed toward methods of treatment of head and neck cancers, wherein the method comprises administering an effective amount of a cannabis extract (CE) comprising CBD, which is provided in a suitable carrier for treatment of the cancer.
- CE cannabis extract
- treatment is provided for squamous cell carcinomas of the head and neck, wherein treatment comprises oral mucosal treatment, intravaginal treatment, rectal suppositories, or combinations thereof.
- the present invention provides a cannabis extract for use in a method of treating head and neck cancer in a patient, wherein said cannabis extract comprises cannabidiol (CBD).
- CBD cannabidiol
- the present invention provides an intravaginal composition for use in a method of treating head and neck cancer in a patient, wherein said intravaginal composition comprises a cannabis extract comprising cannabidiol, and a pharmaceutically acceptable excipient.
- the present invention provides a cannabis extract for use in a method of treating head and neck cancer in a patient, wherein said cannabis extract comprises cannabidiol (CBD) and wherein said method is a method for concurrently treating head and neck cancer and the method comprises administering the cannabis extract to the patient concomitantly via an oral formulation and via an intravaginal formulation.
- CBD cannabidiol
- the term “concomitantly” means that the oral formulation and the intravaginal formulation are administered to the patient no more than 72 hours apart, preferably no more than 48 hours apart, and more preferably no more than 24 hours apart, for example no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours, apart, no more than 3 hours apart, no more than 2 hours apart, no more than an hour apart, no more than 30 minutes apart, or simultaneously.
- the present invention provides an oral formulation for use in a method for concurrently treating head and neck cancer wherein said oral formulation comprises a cannabis extract comprising cannabidiol (CBD) and a pharmaceutically acceptable excipient, and said method comprises administration of the oral formulation concomitantly with an intravaginal formulation comprising a cannabis extract comprising cannabidiol (CBD) and a pharmaceutically acceptable excipient.
- said oral formulation comprises a cannabis extract comprising cannabidiol (CBD) and a pharmaceutically acceptable excipient
- CBD cannabidiol
- the present invention provides an intravaginal formulation for use in a method for concurrently treating head and neck cancer wherein said intravaginal formulation comprises a cannabis extract comprising cannabidiol (CBD) and a pharmaceutically acceptable excipient, and said method comprises administration of the intravaginal formulation concomitantly with an oral formulation comprising a cannabis extract comprising cannabidiol (CBD) and a pharmaceutically acceptable excipient.
- said intravaginal formulation comprises a cannabis extract comprising cannabidiol (CBD) and a pharmaceutically acceptable excipient
- the present invention provides a cannabis extract for use in a method of treating head and neck cancer wherein said cannabis extract comprises cannabidiol (CBD) and wherein said method comprises coadministering to a patient an effective amount of said cannabis extract and an effective amount of a chemotherapeutic agent.
- CBD cannabidiol
- the term “coadministering” means that the cannabis extract and the chemotherapeutic agent are administered to the patient no more than 72 hours apart, preferably no more than 48 hours apart, and more preferably no more than 24 hours apart, for example no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours, apart, no more than 3 hours apart, no more than 2 hours apart, no more than an hour apart, no more than 30 minutes apart, or simultaneously.
- the present invention provides a chemotherapeutic agent for use in a method of treating head and neck cancer wherein said method comprises coadministering to a patient an effective amount of said chemotherapeutic agent and an effective amount of a cannabis extract, wherein said cannabis extract comprises cannabidiol (CBD).
- CBD cannabidiol
- the present invention provides a pharmaceutical composition for use in a method of treating a head and neck cancer wherein said pharmaceutical composition comprises a cannabis extract and an effective amount of CBD.
- the present invention provides the use of a cannabis extract comprising cannabidiol (CBD) in the manufacture of a medicament for use in a method of treating head and neck cancer.
- CBD cannabidiol
- the present invention provides the use of an intravaginal composition comprising a cannabis extract comprising cannabidiol, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for use in a method of treating head and neck cancer.
- the present invention provides the use of a cannabis extract comprising cannabidiol (CBD) in the manufacture of a medicament for use in a method of treating head and neck cancer wherein said cannabis extract is coadministered with a chemotherapeutic agent.
- CBD cannabidiol
- the present invention provides the use of a chemotherapeutic agent in the manufacture of a medicament for use in a method of treating head and neck cancer wherein said chemotherapeutic agent is coadministered with a cannabis extract comprising cannabidiol (CBD).
- CBD cannabidiol
- the present invention provides the use of a pharmaceutical composition comprising a cannabis extract and an effective amount of CBD in the manufacture of a medicament for use in a method of treating a head and neck cancer.
- CBD cannabidiol
- the cannabis extract for use wherein said cannabis extract is selected from a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), a CBD isolate, and cannabidiolic acid (CBD A), optionally wherein the BSHE or FSHE comprises (i) from 50% to 99% by weight of CBD and (ii) at least one other cannabinoid selected from A-9-tetrahydrocannabinol ( ⁇ 9 -THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), A-8-tetrahydrocannabinol cannabichromene (CBC), cannabichromene acid (CBCA), cannabigerol (CBG), cannabigerol acid (CBGA), cannabidiolic acid (CBD A), cannabidivarin (CBDV), cannabinol (CBN), cannabicyclol (CBL), and combinations
- the cannabis extract for use wherein said cannabis extract comprises between 10 mg and 500 mg CBD per dose.
- the cannabis extract for use wherein: (a) the method comprises administration of the cannabis extract to the patient via an oral dose, oral mucosal dose, intravaginal dose, or combinations thereof; and/or (b) the method comprises administration of a dose of the cannabis extract to the patient at least once every three days, preferably at least once a day, at least twice a day, or at least three times a day; and/or (c) the method comprises administration of an amount of the cannabis extract sufficient to generate a concentration of at least 10 ⁇ g/mL of the cannabis extract at a target tissue in the patient, preferably wherein the target tissue is a cancerous tissue of a female reproductive tract; and/or (d) the method comprises administration of an amount of the cannabis extract sufficient to reach an effective therapeutic level as measured through systemic plasma levels of CBD; and/or (e) the method comprises administration of between 20 mg and 4,250 mg of CBD to the patient per day; and/or (f) the cannabis extract is formulated at an acidic pH, preferably at
- the cannabis extract for use wherein: (a) the head and neck cancer has metastasized; and/or (b) the head and neck cancer is a chemoresistant cancer.
- the cannabis extract for use wherein said cannabis extract comprises between 1% and 99.9% CBD and wherein the method comprises administering the cannabis extract to the patient via intravaginal administration, preferably wherein: (a) the cannabis extract comprises between 60% and 99.9% CBD; and/or (b) the cannabis extract is selected from a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), and a CBD isolate; and/or (c) the cannabis extract comprises CBDA.
- FSHE full spectrum hemp extract
- BSHE broad spectrum hemp extract
- CBD isolate a CBD isolate
- a mucosal composition for use in a method of treating head and neck cancer in a patient wherein said mucosal composition comprises a cannabis extract and a pharmaceutically acceptable excipient.
- the mucosal composition for use wherein the composition comprises (i) an oil or fat as a carrier and/or (ii) at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient, or a combination thereof, optionally wherein the at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient, or combination thereof make up between 1% and 50% by weight of the total weight of the composition, further optionally wherein: the terpene is selected from ⁇ -myrcene, ⁇ -caryophyllene, linalool, ⁇ -pinene, citral, D-limonene, eucalyptol, and combinations thereof; and/or the polyphenol is selected from a catechin, quercetin, cannflavin A/B/C, rutin, chlorogenic acid, and combinations thereof; and/or the essential fatty acid is selected from an omega 3 acid
- the mucosal composition for use wherein: (a) the mucosal composition comprises a dose of between 25 mg and 4,250 mg CBD and the method comprises administering the composition to the patient via insertion to a mucosal surface selected from oral mucosa, rectum, vagina, or nasal passages; and/or (b) the method comprises administering at least two doses of the mucosal composition to the patient per day, wherein each dose of the mucosal composition comprises between 10 mg and 2,125 mg cannabis extract; and/or (c) the mucosal composition has an acidic pH, preferably a pH between 3.5 and 6.
- the cannabis extract for use wherein said method is a method for treating head and neck cancer and the method comprises administering the cannabis extract to the patient concomitantly via a mucosal formulation, preferably wherein the cannabis extract is a full spectrum hemp extract (FSHE) or a broad spectrum hemp extract (BSHE).
- FSHE full spectrum hemp extract
- BSHE broad spectrum hemp extract
- the cannabis extract for use wherein said method comprises coadministering to a patient an effective amount of said cannabis extract and an effective amount of a chemotherapeutic agent.
- a chemotherapeutic agent for use in a method of treating head and neck cancer wherein said method comprises coadministering to a patient an effective amount of said chemotherapeutic agent and an effective amount of a cannabis extract.
- the cannabis extract for use or a chemotherapeutic agent for use wherein: (a) the chemotherapeutic agent is selected from paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, fluorouracil, methotrexate, cetuximab, and combinations thereof; and/or
- the head and neck cancer is a chemoresistant cancer; and/or (c) the method comprises a first step of determining chemoresistance of a cancerous tissue in a patient and a subsequent step of administering to the patient an effective amount of the cannabis extract and an effective amount of the chemotherapeutic agent upon confirmation of chemoresistance; and/or (d) the effective amount of the chemotherapeutic agent is at least 50% less than an indicated dose of the chemotherapeutic agent when administered in the absence of the cannabis extract; and/or (e) the method comprises administering the cannabis extract to the patient in an amount of between 20 mg and 4,250 mg per day.
- compositions for use in a method of treating head and neck cancer wherein the composition comprises between 1% and 99% by weight of a CE.
- a composition wherein the CE of the composition comprises (a) a FSHE, a BSHE, a CBD isolate, and/or a CBDA isolate; and/or (b) wherein the composition comprises a carrier at between 1% and 99% by weight of the composition; and/or
- composition further comprises one or more excipients at between 1% and 50% by weight of the composition.
- a composition for treatment of head and neck cancer comprising a cannabis extract (CE), wherein the CE comprises between 1% and 100% by weight of the composition and all percentages therein.
- the CE comprises between 10% and 90% by weight, or 20% by 90% by weight, and preferably between 40% and 80% by weight of the composition.
- the CE is preferably a BSHE, a FSHE, a CBD isolate, or a CBDA isolate. In each of these different CE, the BSHE, the FSHE, the CBD isolate, or the CBDA isolate, they make up between 50% and 99.9% by weight of the CE, with the remaining being waxes, fats, fatty acids and the like.
- preferred embodiments utilize a carrier at between 1% and 99% by weight of the composition, and preferably, one or more additional excipients depending on the use case of the composition.
- the composition is typically then administered based upon the dosage in mg of CBD being administered. Wherein the amount of the composition required to meet that mg of CBD depends on the quantity of CBD within each of the CE.
- a method of treatment of a head and neck cancer comprising administering to a patient in need thereof, an effective amount of a composition according to any one of the preceding embodiments.
- the effective amount is between 20 mg and 4,250 mg of cannabidiol (CBD).
- a pharmaceutical composition for use in a method of treating a head and neck cancer wherein said pharmaceutical composition comprises a cannabis extract comprising an effective amount of CBD.
- the pharmaceutical composition for use wherein the composition further comprises: (a) a carrier; and/or (b) at least one additional cannabinoid selected from CBDV, THC, CBG, CBN, CBC, CBDA and combinations thereof; and/or (c) at least one terpene, preferably wherein the terpene is selected from ⁇ -myrcene, ⁇ -caryophyllene, linalool, ⁇ -pinene, citral, D-limonene, eucalyptol, and combinations thereof; and/or (d) at least one polyphenol, preferably wherein the polyphenol is selected from a catechin, quercetin, cannflavin A/B/C, rutin, chlorogenic acid, and combinations thereof; and/or (e) an essential fatty acid, preferably wherein the essential fatty acid is selected from an omega 3 acid, an omega 6 acid, an omega 9 acid, and combinations thereof; and/or (f) a phytonutrient
- a method for treating head and neck cancer comprising: administering to a patient and effective amount of a composition comprising a cannabis extract (CE).
- CE cannabis extract
- the method wherein the CE comprises between 50% and 99.9% cannabidiol (CBD).
- CBD cannabidiol
- the method wherein the CE is selected from the group consisting of: a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), a CBD isolate, and a cannabidiolic acid (CBDA) isolate.
- the method wherein the CE is administered via an oral form, oral mucosal form, intravaginal form, nasal mucosal form, rectal form, injectable form, or combinations thereof.
- the method wherein the effective amount of the cannabis extract comprising CBD comprises between 10 mg and 4,250 mg of CBD per day.
- administration of the CE is a dose given at least once a day, at least twice a day, or at least three times a day.
- the method wherein the head and neck cancer is a grade 1, grade 2, or grade 3 cancer.
- the method wherein the head and neck cancer is a chemoresistant head and neck cancer.
- the method wherein the CE comprises CBDA at a concentration of between 0.1% and 10%.
- the CE is a BSHE or FSHE and wherein each of the BSHE or FSHE comprises 50% to 99% by weight of CBD and at least one other cannabinoid at a concentration of 0.1% to 10% wherein the at least one other cannabinoid is selected from the group consisting of: ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL, and combinations thereof.
- the CE comprises CBD at a concentration of between 60% and 99%, and at least one other cannabinoid at a concentration of 0.1% to 10% wherein the at least one other cannabinoid is selected from the group consisting of: ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL, and combinations thereof; and wherein the CE comprises a total concentration of cannabinoids of between 65% and 99%.
- the method wherein the composition comprises at least one additional compound selected from the group consisting of: a terpene, a polyphenol, an essential fatty acid, a phytonutrient, and combinations thereof; and wherein the at least one additional compound makes up between 0.1% and 50% of the total weight of the composition.
- the method wherein the composition comprises an oil or a fat as a carrier.
- the method wherein the effective amount of the composition is an amount sufficient to reach an effective therapeutic level of CBD as measured through systemic plasma levels.
- the method wherein the composition is administered at an acidic pH.
- the method wherein the acidic pH is between 3.5 and 6.
- a method of treatment of head and neck cancer comprising administering to a patient an effective amount of a chemotherapeutic agent and coadministering an effective amount of a cannabis extract (CE).
- the method wherein the chemotherapeutic agent and the CE are administered as one composition or as two different compositions.
- the method wherein the chemotherapeutic agent is selected from the group consisting of: paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, fluorouracil, methotrexate, cetuximab, and combinations thereof.
- the method wherein the composition comprising the CE is a composition for oral, rectal, intravaginal, oromucosal, or nasal delivery.
- the method wherein the effective amount of the composition is sufficient to reach an effective therapeutic level as measured through systemic plasma levels of CBD.
- the method wherein the head and neck cancer is a chemoresistant cancer.
- the method wherein the effective amount of a chemotherapeutic agent is at least 50% less than an indicated individual dose and wherein the CE is administered at between 20 mg and 4,250 mg per day.
- the method wherein the cannabis extract is administered in a composition at an acidic pH.
- the method wherein the acidic pH is between 3.5 and 6.
- the method comprising a first step of determining chemoresistance of a cancerous tissue from said patient and administering to the patient an effective amount of the CE upon confirmation of chemoresistance.
- the method wherein the CE comprises a cannabinoid selected from the group consisting of: ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL, and combinations thereof.
- the method further comprising at least one terpene.
- the method wherein the terpene is selected from the group consisting of: ⁇ -myrcene, ⁇ -caryophyllene, linalool, ⁇ -pinene, citral, D-limonene, eucalyptol, and combinations thereof.
- the method further comprising at least one polyphenol.
- the method wherein the polyphenol is selected from the group consisting of: catechins, quercetin, cannflavin A/B/C, rutin, chlorogenic acid, and combinations thereof.
- the method further comprising an essential fatty acid selected from the group consisting of: an omega 3, an omega 6, an omega 9, and combinations thereof.
- the method further comprising a phytonutrient.
- the phytonutrient is selected from the group consisting of: a tocopherol, a sterol, carotene, an aliphatic alcohol, a mineral, and combinations thereof.
- the method wherein the CBD is derived from a phytocannabinoid derived from a cannabis extract.
- a method of treating head and neck cancer comprising:
- a method of treating head and neck cancer comprising: (a) taking a squamous cell from the head, neck, face, or nose from a patient and forming at least one organoid from the squamous cell; (b) performing a screen on the at least one organoid to determine a chemotherapeutic drug responsive to the patient’s organoid; and (c) administering to the patient the chemotherapeutic drug with an effective amount of a composition comprising a cannabis extract (CE) having between 50% and 99.9% CBD.
- CE cannabis extract
- the method wherein the CE is administered to the patient as an oral form, oromucosal form, nasal form, rectal form, intravaginal form, injectable form, or combinations thereof.
- the method wherein the CE is administered oromucosally and intravaginally.
- a composition for use in a method of treating head and neck cancer wherein the composition comprises between 1% and 99% by weight of a cannabis extract (CE).
- CE cannabis extract
- the composition wherein the CE of the composition comprises: (a) a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), a CBD isolate, a CBDA isolate, or combinations thereof; and/or (b) wherein the composition comprises a carrier at between 1% and 99% by weight of the composition; and/or (c) wherein the composition further comprises one or more excipients at between 1% and 50% by weight of the composition.
- compositions for treatment of head and neck cancer wherein the composition comprises a cannabis extract (CE), wherein the CE comprises between 1% and 100% by weight of the composition and all percentages therein.
- CE cannabis extract
- the composition wherein the CE comprises between 10% and 90% by weight, or between 20% and 90% by weight, and preferably between 40% and 80% by weight of the composition.
- the composition wherein the CE is preferably a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), a CBD isolate, or a CBDA isolate.
- FSHE full spectrum hemp extract
- BSHE broad spectrum hemp extract
- CBDA isolate CBDA isolate
- the composition wherein the BSHE and/or the FSHE and/or the CBD isolate and/or the CBDA isolate constitute between 50% and 99.9% by weight of the CE.
- the composition comprising a carrier at between 1% and 99% by weight of the composition.
- composition further comprising at least one or more additional excipients.
- composition wherein the composition is a mucosal composition.
- composition comprising between 20 mg and 4,250 mg of CBD.
- a method of treatment of a head and neck cancer comprising administering to a patient in need thereof a composition in an effective amount.
- the method wherein the effective amount is between 20 mg and 4,250 mg of cannabidiol (CBD).
- FIGS. 1A, IB, 1C, ID, IE, IF, 1G, 1H, and II depict endometrial cancer cells being treated with a cannabis extract comprising CBD, with FIG. 1 A showing a diagram of the process of capturing the data regarding protein expression, FIG. IB depicting protein differentiation numbers; FIG. 1C depicting upregulated and down regulated cells in the vehicle and with a cannabis extract comprising CBD treatment; FIG. ID depicting the top 20 up and down regulated proteins in treated endometrial cancer cells; and FIG. IE depicting the cannabis extract’s effects on signaling and trafficking of various physiological and pathophysiological pathways.
- FIG. IF depicts the percent of patients in which CB1 receptors are implicated in progression or management of the disease; FIG.
- FIG. 1G depicts the percent of patients in which Cannabinoid receptor 2 is implicated in progression or management of disease
- FIG. 1H depicts cannabinoid receptor 1 protein expression in an endometrial cancer cell
- FIG. II depicts cannabinoid receptor 2 protein expression in an endometrial cancer cell.
- FIG. 2A and 2B depict endometrial cancer based organoids treated with a cannabis extract, with FIG. 2A depicting cells treated with varying concentrations of cannabis extract as delivered through a BSHE.
- FIG. 2B graphically summarizes the results showing a virtual eradication of the endometrial cancer organoids at as low as 10 ⁇ g/mL, and all values above.
- FIGS. 3A and 3B depict grade 3 endometrial cancer organoids being treated with 2, 3, 4, 5, 7, or 10 ⁇ g/mL of a cannabis extract (BSHE) and the percent in decrease in the number of organoids; with FIG. 3A detailing 2, 3, 4, and 5 ⁇ g/mL and FIG. 3B detailing 3, 5, 7, and 10 ⁇ g/mL dose.
- BSHE cannabis extract
- FIGS. 4 A and 4B depict human head and neck cancer organoids being treated with three different cannabis extracts, namely, broad spectrum hemp extract (BSHE), full spectrum hemp extract (FSHE), and CBD isolate.
- FIG. 4A details that head and neck cancers showed a viability of about 10% or less at a concentration of 10 ⁇ g/mL for two cannabis extracts. Notably, viability at 10% or less is considered at or close to zero, because of the background noise in the assay test.
- FIG. 4B shows the use of CBDA, with concentrations at 0, 1, 5, 10, 15, 20, 25, 35, and 50 ⁇ g/mL. Again, the results between about 15 and 50 ⁇ g/mL are somewhat indistinguishable due to the sensitivity of the counting system at the lowest levels.
- FIG. 5 depicts a graphical chart of endometrial cancer tumor volumes within mice, wherein the mice were injected with patient derived endometrial cancer cells.
- the data shows the change in tumor volume from day 7 to day 21 and depicting the therapeutic efficacy of the various cannabis extracts on the tumor volumes.
- Mice were treated with a quantity of 30 mg/kg body weight for each of the cannabis extracts, or approximately 170 mg/day of an equivalent human dose.
- FIG. 6 details head and neck cancer organoids response to paclitaxel or a combination of paclitaxel and a cannabis extract, at 4, 16, and 20 nm/mL concentration, with an IC50 dose of the cannabis extract.
- use of the lowest dose of paclitaxel with an IC50 amount of CE provides a superior response than any concentration of paclitaxel alone.
- FIG. 7 details the impacts of carboplatin alone or with a cannabis extract on grade 2 endometrial cancer organoids at 50, 100 and 250 pm/mL carboplatin dose.
- adding CE to carboplatin dramatically improves the kill rate of the composition, essentially taking ineffective treatments with carboplatin alone into a complete treatment, with just a low IC50 dose of each of the different CE products.
- FIG. 8 details paclitaxel based tests on mice models, showing that at day 21, the impacts of the combination of paclitaxel and the cannabis extract are significantly better than paclitaxel alone. Where the combination therapy continues to reduce tumor volume, while the paclitaxel alone becomes ineffective at reducing tumor growth over time.
- FIG. 9A and 9B depict histopathology taken from the mice models show that treating the mice with cannabis extracts does not damage the cells of the ovary, fallopian tube, uterus, vagina, or the liver.
- FIG. 10 depicts the effects of pH modification of the cannabis extract when applied at the same concentration to a cancer organoid.
- native pH is approximately 10.85 and the ability to reduce viability is worse at pH of 10 and 8, than at native pH, and surprisingly more potent at pH of 4.
- the term “about” means plus or minus 5% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45% - 55%. Thus, 20 mg means the range of 19 - 21, inclusive of the endpoints and all numbers in between.
- administering when used in conjunction with a therapeutic means to administer a therapeutic directly to a subject, whereby the agent positively impacts the target.
- administering the therapeutic drug or compound may be accomplished by, for example, injection, oral administration, topical administration, mucosal administration and/or in combination with other known techniques.
- the administering techniques may further include heating, radiation, chemotherapy, ultrasound, and the use of delivery agents.
- the administration is through oral, oral mucosal/sublingual, nasal, intramuscular, rectal, and/or intravaginal dosage forms.
- intravaginal forms are intended to be inserted into the vagina, typically with a carrier, wherein the active ingredients pass through the vaginal mucosal membrane.
- the active ingredients may also be provided in an oral form, to be swallowed.
- Another oral form is an oral mucosal application, which is often provided as a sublingual application, which, while it is ultimately swallowed to enter the stomach, is intended to be held in the mouth, for example under the tongue, and the active ingredients pass through the oral mucosal membrane before being swallowed or passed into the stomach by salivary action or active swallowing of the materials or both.
- pharmaceutically acceptable it is meant that the components including, but not limited to the carrier, diluent, adjuvant, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- pharmaceutical composition is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions of the present invention encompass any composition made by admixing a compound or compounds of the present invention and a pharmaceutically acceptable carrier.
- agent means a compound or composition utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient.
- agent active agent
- therapeutic agent therapeutic agent
- a “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to inhibit, block, or reverse the activation, migration, proliferation, alteration of cellular function, and to preserve the normal function of cells.
- the activity contemplated by the methods described herein includes both medical therapeutic and/or prophylactic treatment, as appropriate, and the compositions of the invention may be used to provide improvement in any of the conditions described. It is also contemplated that the compositions described herein may be administered to healthy subjects or individuals not exhibiting symptoms but who may be at risk of developing a particular disorder.
- a therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue to achieve the therapeutic response.
- the therapeutic shall be effective in treating cancerous growths related to head and neck cancer, and metastatic disease relating thereto.
- treat refers to both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results.
- beneficial or desired results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder, or disease such as a reduction in the size of a tumor; stabilization (i.e., not worsening) of the state of the condition, disorder, or disease; delay in onset or slowing of the progression of the condition, disorder, or disease; amelioration of the condition, disorder, or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder, or disease.
- CANNABIS EXTRACT is a composition derived from the Cannabis genus of plants (including hemp).
- a cannabis extract contains cannabidiol, and more typically comprises both cannabidiol (CBD) and at least one additional cannabinoid, selected from the group consisting of ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL, and combinations thereof at between 0.1% and 40%.
- Cannabis extracts according to the present invention are typically enriched in cannabidiol, and may comprise between 1% and 99.9% CBD, preferably between 20% and 99.9% CBD, more preferably between 50% and 99.9% CBD, even more preferably between 70% and 99.9% CBD, and most preferably between 90 and 99.9% CBD.
- Full spectrum hemp extract, broad spectrum hemp extract, CBD isolate, and CBDA isolate are forms of cannabis extract utilized herein, as non-limiting examples of the CE.
- the term CBD is often used interchangeably with CE, to mean the CE product containing the particular amount of CBD. while in other instances, which are obvious to the reader, the CBD refers to a CBD isolate, which means the CE was processed to remove and isolate CBD, removing virtually all other components of the CE.
- the term FULL SPECTRUM HEMP EXTRACT is a composition derived from the Cannabis genus of plants which contains CBD, and quantities of THC above 0, preferably, between 0.01 and 5%, most preferably being between 0.01% and 0.3%.
- the FSHE may comprise additional cannabinoids, yielding a product that comprises at least 50-99% CBD, at least 0.01% to 10% THC ( ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC), and total cannabinoids of between 50% and 99% of the weight of the CE.
- BHSE BROAD SPECTRUM HEMP EXTRACT
- CBD BROAD SPECTRUM HEMP EXTRACT
- BHSE comprises between 60 and 99.9% CBD and least one additional cannabinoid, selected from the group consisting of ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC, CBC, CBCA, CBG, CBGA, CBD A, CBDV, CBN, CBL, and combinations thereof at between 0.1 and 40%.
- Head and neck cancers are particularly nefarious, as tumors lead to damaging impacts on the throat and body as a whole, making ordinary eating, breathing, and speaking difficult.
- Such cancers include, but are not limited to: esthesioneuroblasoma, mouth cancer, lip cancer, nasal and paranasal tumors, nasopharyngeal carcinoma, pituitary tumors, salivary gland tumors, skin cancer, soft palate cancer, throat cancer, thyroid cancer, tongue cancer, tonsil cancer, and others.
- Head and neck cancers develop from tissues in the lip, oral cavity, larynx, salivary glands, nose, sinuses, or the skin of the face.
- Symptoms of these cancers in the mouth typically include sores in the mouth that do not heal, swelling in the jaw, unusual bleeding in the mouth, and lumps in the mouth.
- symptoms may include trouble breathing or speaking, a lump or swelling, trouble chewing or swallowing, difficulty in clearing the throat, acute pain, and ringing in the ears.
- symptoms include blocked sinuses that won’t clear, sinus infections that won’t clear, bleeding, headaches, swelling and pain around the eyes, and pain in the upper teeth.
- Roughly 90% of head and neck cancers are pathologically classified as squamous cell cancers. [0102] Head and neck cancers frequently arise due to occupational relationships and tobacco or alcohol use.
- Treatment of head and neck cancers frequently includes chemotherapy, radiation therapy, and resection of the tumors to seek to prevent metastases of the cancer throughout the body. These treatments are both effective at killing cancerous tumor cells but also are highly toxic to the surrounding healthy tissues. It is well-known that chemotherapy agents are indiscriminate in their killing, and thus significant secondary impacts occur to the patient leading to impacts on the quality of life from damage to healthy tissues. Indeed, even where the chemotherapy is effective in treating the cancer, the toxic effects of the chemotherapy often prove fatal overtime. In a recent study, use of chemotherapy to treat cancer, hastened death in 27% of cases. In a further study, 43% of cancer patients receiving chemotherapy show significant treatment-related toxicity, despite receiving other parallel treatments to reduce the side effects of the chemotherapy.
- chemotherapy is given in a cycle, meaning a drug or combination of drugs are given for a period of usually 2-6 weeks, and then a rest period, followed by a second or more treatment period.
- Drugs that are currently utilized for head and neck cancer treatment including paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, fluorouracil, methotrexate, cetuximab, and the combined therapy of carboplatin or cisplatin with paclitaxel, and others.
- Cisplatin in particular, is often given as part of chemoradiation, wherein the chemotherapy is combined with radiation therapy.
- Chemotherapy drugs typically fall into different classes of drugs, an alkylating agent, an antimetabolite, ant-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, DNA repair enzyme inhibitors, plant alkaloids, and antineoplastics.
- Paclitaxel is an antineoplastic - plant alkaloid
- Docetaxel is an antineoplastic - plant alkaloid
- Doxorubicin is an antineoplastic - anthracycline antibiotic
- Carboplatin is an antineoplastic - alkylating agent and platinum based
- cetuximab is a monoclonal antibody - epidermal growth factor receptor inhibitor
- methotrexate is an immune-system suppressant
- fluorouracil is cytotoxic chemotherapy
- Cisplatin is an antineoplastic - alkylating agent and platinum based.
- paclitaxel is given in combination with one or more of cisplatin or carboplatin.
- platinum-based chemotherapy the majority relapse, and the term “platinum-resistant” refers to patients with head and neck cancers who progress within six-months of platinum-based therapy. These patients are at the highest risk for disease related mortality. Even with aggressive treatment and especially when not detected until metastases, leading to low survival rates at 2 and 5 years past initial diagnosis and treatment.
- Chemoresistance of which platinum resistant is one variety, is defined as simply that the cancer cells are resistant to the action of the particular therapeutic agent, such that the disease progresses. Chemoresistant disease may still have some clinical response, but not at sufficient levels to prevent disease progression, or would require such high doses to make the treatment unsuitable. Chemosensitive, therefore being the opposite, wherein the cancer cells in a patient are sensitive to the chemotherapy agent, so that the disease is managed or reduced. However, cancers may at one point respond to the chemotherapy and become chemoresistant as treatment progresses through a typical on/off cycle. Indeed, presently, where chemoresistant tumors exist, there are few, if any treatment plans other than palliative care, or additional removal upon the identification of tumors.
- ECC endometrial cancer cells
- CE endometrial cancer cells
- CBD CBD (1 ⁇ g/mL
- LC liquid chromatography
- MS/MS tandem mass spectrometry
- FIG. IB the Venn diagram shows the results of LC- MS/MS analysis which is that treated cells expressed 2,842 different proteins than untreated cells, untreated cells expressed 2,681 different proteins than treated cells, and treated and untreated both expressed 3,747 common proteins.
- FIG. 1C compares the degree to which certain proteins were expressed (or not expressed) in untreated cells and treated cells.
- FIG. ID of the thousands of proteins that were differentially expressed with treated and untreated cells, the top 20 upregulated (e.g., in treated cells only) and downregulated (e.g., in untreated cells only), are identified and enumerated.
- FIG. IE the effect of treatment with CE with CBD on signaling and trafficking of various physiological and pathophysiological pathways is shown.
- proteins associated with Endocannabinoid Neuronal Synapse are shown to be upregulated in untreated cells and downregulated in treated cells.
- FIGS. IF and 1G shows the conservation across several different cancer types wherein each of cannabinoid receptor 1 and 2 are implicated in disease.
- FIG. IF and 1G shows the conservation across several different cancer types wherein each of cannabinoid receptor 1 and 2 are implicated in disease.
- FIG. 1G depicts the same list for the CB2 receptor. Importantly, we can see significant overlap in the CB 1 and CB2 receptor with those of ovarian and endometrial cancers to head and neck cancers.
- FIG. 1H a tissue sample taken from a patient with endometrial cancer was selectively stained to show CB1 receptor expression.
- FIG. II is a similar tissue sample selectively stained to show CB2 receptor expression.
- organoids are miniature structures that emulate organs in all their complexity. They are derived from stem cells collected via biopsies and/or resected healthy tissues or tumors. In culture, they self-organized into three-dimensional tissues that mimic the tissues of the individual patient from which they were derived. That is, organoids have the same genetic instructions as the individual from which they were derived and thus demonstrate identical mutations, proliferation, and disease progression as their human counterpart.
- Organoids can be made to replicate organs with differentiated cell types or to express selected aspects of identified cells of interest. Unlike traditional cell line models associated with high failure rates in clinical trials, organoids’ responses precisely and directly translate to human responses. Organoids are well established and have already transformed medical research in providing breakthroughs in treating cystic fibrosis, pancreatic cancer, diabetes, and other diseases.
- organoids as clones of an individual’s organ. In essence, it is a living, growing avatar of a distinct patient existing outside the body. The avatar will mimic tumor growth and respond to treatment cancer just as it would inside the body.
- This personalized replica identifies allows for identification of individualized, targeted treatment in a matter of days. It allows a patient to avoid wasting time and risking toxicity with ineffective therapies.
- FIG. 2A depicts images of the human endometrial cancer organoids treated with different doses of a cannabis extract, in particular a broad spectrum hemp extract (BSHE) comprising CBD. Concentrations are noted for the quantity of CBD in each of the doses with DMSO as the vehicle for all tests. Each of the tests were run in at least triplicate, including the carrier alone.
- BSHE broad spectrum hemp extract
- FIGS. 2 A depicts images of patient derived organoids, being treated with a vehicle, 1 ⁇ g/mL, 10 ⁇ g/mL, 25 ⁇ g/mL, and 50 ⁇ g/mL.
- both the vehicle/control and the 1 ⁇ g/mL concentration were unable to destroy the cancer cells, but at a concentration as low as the 10 ⁇ g /mL, and including higher doses at 25 and 50 ⁇ g/mL, the BSHE was able to completely kill the organoid based cancer cells.
- FIG. 2B shows the absence of organoids at any of the last three datapoints, thus showing that the number of organoids is zero for all samples treated with 10 ⁇ g/mL or higher dose of CBD.
- CBD CBD
- a patient of 1 ⁇ g/mL is a dose of approximately 20 mg a day of CBD
- 10 ⁇ g/mL is approximately 200 mg a day
- 25 ⁇ g/mL is approximately 500 mg a day
- 50 ⁇ g/mL is approximately 1000 mg a day.
- the prescribed CBD isolate is given at a dose of between 5 and 50 mg of CBD/kg and in the United States an average weight of between 65 and 85 kg, yields doses of between 325 to 4250 mg a day of CBD. Applicant’s actual tests, therefore, range from well below these doses to about % of the acceptable dose.
- organoids from endometrial cancer were able to show a dramatic reduction in the number of cancers derived organoids as compared to the vehicle at concentrations as low as 2 ⁇ g/mL, and in each case, as low as 7 ⁇ g/mL for complete reduction in the organoids in a sample regardless of the grade of the endometrial cancer. Therefore, application of cannabis extracts comprising CBD are effective in reducing the number of viable patient derived organoid cells from endometrial cancer. These results were confirmed across each of the three grades of endometrial cancer and also with organoids derived from ovarian cancer, which are not shown, but were performed in a side-by- side testing.
- CBD as applied through a CE was thus effective in destroying the organoids in these gynecological cancers, including three grades of endometrial cancer, ovarian cancer, as well as chemoresistant ovarian cancers. This response held regardless of the severity or grade of the cancer. Because of the significant overlap between gynecological cancers and head and neck cancers in protein signaling, as detailed in FIG. 1, Applicant determined that the successes in these gynecological cancer based organoids was also likely to be effective for head and neck cancers.
- FIG. 4A details the trials of BSHE, FSHE, and CBD isolate at concentrations of 0 (control) 1, 2, 3, 4, 5, 7, and 10 ⁇ g/mL to determine a percent viability of the head and neck cancer organoids.
- dosing at or about 10 ⁇ g/mL of the cannabis extract was effective in reducing the viability of the head and neck cancer organoids significantly, and in several cases down to or below 10% viability, in which the sensitivity of the assay does not precisely determine viability based on the background cells.
- Less than 10% viability is considered 95-100% cell death in these experiments due to residual signaling from dead cells and Matrigel.
- FIG. 4B confirms much the same, with a CBDA cannabis extract, which requires a slightly higher concentration, to at least 15 ⁇ g/mL before the percent viability drops below 10%.
- a very large jump in viability is seen at between 10 and 15 ⁇ g/mL for the head and neck cancer organoid cells.
- FIGS. 4A and 4B confirm that the head and neck cancer organoids respond in parallel to the response found in the prior trials with endometrial cancer organoids. This allows for further investigation with additional endometrial cancer lines to shed light on the efficacy of the head and neck organoids.
- FIG. 5 depicts the results over the 21-day period of testing with administration of 30 mg/kg of four different CBD types. The mice tests were performed according to the protocol in the method section, below.
- mice models showed that tumor growth ranged between a slight decrease or slight growth over the first 7 to 10 days, before the tumors as a whole began to decrease in size.
- day 14 in comparison to the control, each of the tumor volumes were at or below their day 0 volume, with significant decreases seen in each of the different cannabis extracts as compared to volume at days 7 and 10.
- day 21 tumor sizes for all of the treated samples are dramatically reduced as compared to both of their original volume and also as compared to control.
- the data in FIG. 5 is shocking in its efficacy.
- the control mice, receiving only the vehicle, show tumor growth of nearly 150%.
- each of the four treated examples show a decrease in tumor volume of between 53 and 82%.
- the differences are literally life and death, as the control tumor reaches a size that requires ethical sacrifice of the animals, while the treated animals show virtually no tumor after just 21 days of treatment.
- This reaffirms the prior organoid studies, which showed that cancer tumors, specifically, those of endometrial cancer and head and neck cancer, are susceptible to treatment with cannabis extracts comprising CBD. Accordingly, Applicant confirms that use of a cannabis extract is suitable to reduce tumor volume, and to reduce viability of tumor cells across several different models.
- Chemotherapy is often given in progressive doses, meaning, it may take more of the chemotherapy drug to obtain the same response, as disease progresses. In many cases, patients progress wherein the ovarian cancer becomes chemoresistant, which requires a change in the chemotherapy agent or a completely new approach toward managing the disease.
- the combination of CBD with chemotherapeutic agents could lead to a reduction in the quantity of chemotherapeutic agents needed to achieve a reduction in the tumor cells. Therefore, Applicant tested the combination of chemotherapy drugs with a cannabis extract to determine if the combination could reduce the amount of chemotherapy required to obtain therapeutic responses, namely reducing the growth of camcer cells/tumors and ultimately eliminating the tumors.
- chemotherapeutic agents were tested for efficacy against both organoids and then on mice models. Because of the toxic nature of the chemotherapeutic agents, a key metric and value is the ability to generate an equivalent clinical response to the chemotherapy, while using a lower total amount of the chemotherapeutic agent.
- a simplified example would be that if a normal dose of chemotherapy agent X was 200 mg, resulting in a reduction of tumor size by 90%, then the ability to use the same chemotherapy agent X at a dose of 100 mg and obtaining the same reduction of tumor size by 90% would provide significant benefits to the patient with regards to less secondary damage to healthy tissue, and other known impacts from the chemotherapeutic agent.
- FIG. 6 details the use of paclitaxel alone or paclitaxel in combination with a cannabis extract at reducing the viability of head and neck cancer organoids.
- the dosing of the cannabis extract was performed at 50% inhibitory concentration (IC50), so as to provide a better data curve.
- IC50 is conventionally used to determine drug potency with cell-based toxicity tests.
- FIG. 6 depicts paclitaxel alone in black, and a combined therapy in white. The differences in each of the datapoints is striking. However, when viewed closer, the differences are even more profound.
- the paclitaxel alone shows virtually no impact on the organoid viability.
- results can reduce viability to below 30%, with a difference between the paclitaxel alone and the paclitaxel with the cannabis extract being different by about 50% for the lowest does and about 30% for the higher doeses. Indeed, this effectively allows the reduction of the dose of paclitaxel by several fold, yet obtaining a much greater kill rate than any dose of paclitaxel alone.
- the cannabis extract can be administered at a higher dose to further increase the efficacy of the combined treatment.
- Applicant repeated the tests by replacing paclitaxel with carboplatin.
- the surprising findings with paclitaxel were further confirmed by testing the impacts of carboplatin alone or carboplatin with a cannabis extract.
- FIG. 7 three different cannabis extracts were tested, a BSHE a FSHE, and a CBD isolate.
- carboplatin is another first line chemotherapeutic agent for head and neck cancers, and leads to dramatic reduction in viability, to reach viability at or near 10% with certain cannabis extracts and the lowest dose of carboplatin.
- mice were grown, according to the methods below, and tested for tumor response to paclitaxel alone and then to paclitaxel with the cannabis extracts.
- FIG. 8 details the results of mice tumor volume comparing paclitaxel alone to those treated with a combined paclitaxel and a cannabis extract.
- the control, or no treatment data is not shown in FIG. 8, but resulted in almost 150% growth over the 21 days, as compared to the initial tumor volume.
- What is striking is what was seen in the organoid data and then repeated here, by combining a low dose of paclitaxel with an effective dose of any of the cannabis extracts yields dramatically greater reduction in tumor volume as compared to the paclitaxel alone or even the cannabis extracts alone at the given dose.
- No amount of paclitaxel alone was shown to be as effective as any amount of paclitaxel that is combined or coadministered with CBD.
- coadministration of the hemp extract comprising a known amount of CBD with the carboplatin or with the paclitaxel was surprisingly more effective than their administration alone.
- FIG. 8 utilized a dose of just 10 mg/kg, which can be adjusted to 30.007 mg/m 2 of Paclitaxel, and the clinically recommended human dose of Paclitaxel is 175 mg/m 2 .
- the paclitaxel only dose was, in essence ineffective after an initial reduction at day 10. Over the course of the remaining 11 days, the tumor volume in the paclitaxel only mice was not reduced. However, the stasis of the paclitaxel only dose is in stark contrast to the paclitaxel combination with CE.
- Each of the CE products was administered at a concentration of 30 mg/kg, yielding an effective dose of 170.1 mg/day human equivalent.
- each of the tumor volumes for these combination treated mice were at least 20% better in the change in tumor volume than the paclitaxel alone mice. Indeed, for three of the cannabis extracts, the results were almost 40% better in the change in the tumor volume, yielding tumor volumes at almost 80% less than their initial treatment volume. Thus, administering almost % of the normal indicated dose of paclitaxel with a dose of CE resulted in unexpected synergy in reducing tumor volume within the mice.
- the difference would essentially have a chemotherapy course be ineffective, if given alone, or allow for nearly complete eradication of the tumors over the 21 -day period, simply by administering the paclitaxel with a cannabis extract.
- This allows for a low dose of paclitaxel to be administered, instead of a high dose.
- Such reduction in the Paclitaxel dose will help to avoid the unnecessary side-effects of chemotherapeutic agents, and with the joint administration, provide dramatically increased efficacy.
- FIGS. 9A and 9B depict comparisons between untreated cells and treated cells with cannabis extract.
- FIG. 9A depicts the ovary and fallopian tube
- FIG. 9B depicts the uterus, vagina, and liver tissues.
- a visual comparison between the untreated and treated tissues shows that cannabis extracts comprising CBD do not cause secondary or ancillary damage to healthy tissues.
- a further comparison to chemotherapy treated tissues would show significant damage.
- Chemotherapies can even result in secondary cancer over time. Further, chemotherapy is fatal, particularly when used in higher doses. A recent study evaluating this effect concluded that chemotherapy or its side effects directly caused or hastened death in 27% of patients. Additionally, 43% percent of patients in the study suffered significant treatment-related toxicity within just 30 days of receiving chemotherapy and a full 25% of such patients die from the treatment-related toxicity. The data is particular compelling when the study determined that 19% of all deaths were linked to patients who should not have received chemotherapy at all.
- CBD is non-toxic in non-transformed cells and does not affect physiological parameters (heart rate, blood pressure and body temperature), gastrointestinal transit nor psychomotor or psychological functions. Chronic use and doses up to 1,500 mg/day of CBD are established as well tolerated in humans, with some doses even administered at up to 4,250 mg/day in certain applications. CBD dominant cannabis extracts have no potential for abuse or dependence. This was best highlighted during the World Health Organization’s 41st Expert Committee on Drug Dependence held in Geneva, Switzerland in November 2018. Annex 1 from the meeting’s report states “cannabidiol should not be scheduled within the International Drug Control Conventions. Cannabidiol is found in cannabis and cannabis resin but does not have psychoactive properties and has no potential for abuse and no potential to produce dependence.
- FIG. 10 shows that the native pH of the cannabis extracts provided for an approximately 2 or 12% viability for the organoids.
- a control, of the buffer solution at each pH was ineffective at reducing viability on the organoids and thus not depicted.
- increasing the pH led to substantial improvements in efficacy.
- pH of 12, and certainly of 14 are highly corrosive, alkaline concentrations and are not suitable for therapeutic use. Indeed, such a pH would not be isotonic, nor would it be appropriate for intravaginal application.
- the vagina has an acidic pH, which is necessary to maintain the balance of bacteria.
- the cannabis extract is provided intravaginally, nasally, or oromucosally, whereby utilizing a buffer to modify pH to between 2 and 6, yields a superior response, than giving the cannabis extract at its native pH.
- the cannabis extract is provided in a carrier with a pH of between 3.5 and 5.5, and more preferably at between a pH of between 4 and 5.
- Applicant identified that endometrial, ovarian, or head and neck cancers can be targeted by certain applications of cannabis extracts.
- cannabis extracts because of the nature of cannabis extracts, and the known low bioavailability of CBD, in particular.
- oral forms may be suitable, it may be possible to improve bioavailability and thus treatment through mucosal applications, whether through oral, oral mucosal, vaginal mucosal, rectal, or other administration to treat head and neck cancers, or the endometrial or ovarian cancers.
- intravaginal delivery of cannabinoids may result in uptake via the inguinal lymph nodes, leading to additional systemic uptake from the reproductive tract.
- women may have a unique dosing opportunity for head and neck cancers, via an intravaginal dosing form to obtain therapeutically efficacious amounts of the CBD, as provided in a cannabis extract.
- Intravaginal delivery is well studied and considered safe, effective, and well tolerated. Intravaginal delivery avoids gastrointestinal absorption and bypasses first pass metabolism, while facilitating a localized effect and a steady, sustained therapeutic response. Absorption and systemic delivery via vaginal epithelium occurs rapidly with similar lipophilic compounds. Variances in thickness of the vaginal epithelium and vagina fluid characteristics, including pH, presence of cervical mucous, and microbiota, may influence absorption rates and bioavailability. [0152] For all genders, mucosal dosing may be easily administered through the oral mucosa.
- CBD has a maximum plasma concentration of 1.6 hours, but this can be delayed in some individuals.
- Orally delivered CBD has a maximum plasma concentration of about 2.5-5 hours but can be delayed up to 6 hours for some individuals.
- Coadministration with high fat food has been shown to increase Cmax by up to 5-fold concentration.
- head and neck cancers may benefit from the direct application of the cannabis extract into the mouth, wherein cancers may be able to be directly contacted by the CBD, where cancers exist on the lip, within the mouth, in the larynx, and throat.
- the prevalence of lymph nodes in the back of the mouth then allows for more rapid onset and uptake of the CBD systemically.
- CBD delivery via the nasal mucosa results in rapid uptake and a Tinax of approximately 10 minutes.
- Tinax a Tinax of approximately 10 minutes.
- the material passes to the rear of the sinuses, it will pass through the throat and may serve as one of the best ways to reach certain cancers with direct application of the cannabis extract.
- Rectal application may also be suitable for both sexes. Rectal suppository delivery results in an increased bioavailability (51-60%) versus oral routes for CBD.
- mucosal dosing can allow for targeted administration of cannabis extracts to treat both local and also metastatic tumors. Additional dosing may still be accomplished via traditional dosing routes, including but not limited to oral dosage forms, such as a soft gel comprising a cannabis extract. Furthermore, administration may be injected, intramuscularly, or into other suitable tissues for uptake.
- the patient reported significant improvements, including a dramatic reduction in the mucus production.
- the patient was able to fully eat, exercise, including running, which was impossible before the CE treatment, suggesting that the esophageal adeonocarcinoma was being well controlled by the FSHE.
- the patient maintained the FSHE oromucosal dosing, which has allowed the patient to control the esophageal adenocarcinoma over a period of at least 12 months. Accordingly, the cancer remains in sufficient remission to return the patient to significant life activities, without the need for damaging chemotherapy.
- a 31-year old Caucasian female presented with significant pain and discomfort, which upon diagnosis was revealed to be endometrial cancer.
- Patient underwent total hysterectomy bilateral salpingo-oophorectomy followed by five rounds of chemotherapy.
- Each of the first five rounds of chemotherapy was a combined chemotherapy with Paclitaxil/Carboplatin.
- the treatments were ultimately ineffective and she did not proceed with a sixth round due to ineffectiveness of the prior rounds.
- the endometrial cancer was stage IV, and metastasized into metastatic lymph nodes, pulmonary metastases, peritoneal metastases, which was confirmed by PET scans. Metastatic endometrial cancer was confirmed by the presence of cancer growth in distal organs. An organoid was crafted for the patient to assess her response to CBD and alternative chemotherapies after failing seven chemotherapy rounds due to chemoresistance. The organoid demonstrated a significant response to CBD and a partial response to gemcitabine/capecitabine (GemCap), a combination chemotherapy she had not yet been offered.
- the patient’s began using CBD, 30mg of B SHE via oromucosal delivery twice daily along with 75mg of F SHE via intravaginal delivery daily, along with standard protocol GemCap. This resulted in a total daily dose of 135 mg of CBD. The patient’s progress was monitored and confirmed by PET scans.
- Table 1 details metabolic response in the patient’s lymph nodes. After treatment, no new enlarged or hyper metabolic nodes within the neck, chest, abdomen, pelvis, or inguinal regions to suggest new sites of metastatic adenopathy.
- Table 2 details the change in pulmonary metastases. Notably, significant reductions in the size of metastases were documented. Furthermore, no new hypermetabolic pulmonary metastases, no lymphangitis, no pleural or pericardial effusion, no abnormal metabolism in the solid abdominal organs, and no evidence of solid abdominal visceral or metastatic disease on diagnostic CT. Previously demonstrated malignancy ascites in the pelvic region was also documented as near completely resolved. Complete metabolic response in peritoneal deposits. For example, largest deposit inferior to the right lobe of the liver 4 mm no longer measurable on PET. Previously 22x 10 mm, SUV max 7.2). No new hypermetabolic peritoneal deposits. No abnormal metabolism in the brain. No suspicious lesions on the low dose, non-contrast CT. No abnormal metabolism in bone to suggest osseus metastasis.
- Table 3 lists agents that were tested on the patient derived organoids, showing that the majority of agents did not impact the patient’s cancer.
- paclitaxel was shown to be wholly ineffective, and thus the 39% cell death is indicative of the need to greatly increase the cell death for successful treatment.
- treatment for head and neck cancer can be achieved by reducing the size of primary and secondary tumors from the head and neck cancer, with the goal of remission of the cancer due to treatment.
- Treatment may thus include, administering to a patient in need thereof, an effective amount of a cannabis extract.
- the cannabis extract is a BSHE, a FSHE, a CBD isolate derived from a cannabis plant, or a CBDA.
- an effective dose may be between about 20 to about 4250 mg a day of CBD, which may be administered over the course of several doses and in different forms.
- a total of 1000 mg a day dose could be provided by 500 mg a day oromucosal and 500 mg a day intravaginally, to treat a female patient in need thereof, as a non-limiting example.
- a method of treatment comprises a 500 mg a day oromucosal and 200 mg a day oral dose of a cannabis extract, with the dose in milligrams corresponding to the quantity of CBD within the dose. Dosing may be performed by administration through a single route or through multiple routes of administration.
- the cannabis extract comprises a fat or oil as a carrier for intravaginal application, and further comprises at least one terpene.
- the cannabis extract comprises total cannabinoids of between 50 and 99.9 of the cannabis extract.
- the percent of the cannabis extract means that, as in the preceding sentence the total cannabinoids make up between 50 and 99.9% by weight of the cannabis extract.
- CBD makes up at least 60%, and more preferably, at least 65, 70, 75, 80, 85, 90, 95, and 99% of all cannabinoids within a cannabis extract.
- the oromucosal dose is administered within a carrier of a fat or an oil.
- a dose is provided as an oromucosal dose, an intravaginal dose, a nasal mucosal dose, a rectal dose, an oral dose, an intramuscular injection, or an intravenous dose.
- the therapeutic methods herein for treatment of head and neck cancers provide for an oral therapy, an oral mucosal therapy, an intravaginal therapy, a nasal mucosal, an injectable, or a rectal therapy, or combinations thereof.
- an intravaginal therapeutic may be used alone or combined with an oral or oral mucosal therapy, or with a rectal therapy.
- any of the treatment options may be utilized alone or in combination to reach a therapeutic dose for treatment of the particular head and neck cancer.
- the oral mucosal therapy seeks to bypasses first pass metabolism through the oral mucosa and allows for higher bioavailability as compared to oral doses that are swallowed. This is due to partial absorption by the buccal tissues followed by metabolism through the amounts swallowed, and entering the systemic systems through the GI tract. While the uptake of CBD in the oral mucosa has a low rate of permeability over a period of 4-12 hours, and accumulates CBD within the oral mucosa, its uptake is significantly greater than oral absorption in the stomach. This provides for an increase in clinically relevant plasma levels for systemic absorption.
- CB receptors 1 and 2 are implicated in numerous head and neck cancers.
- CB1 is implicated with nearly 80% of patients having thyroid cancer, and generally 50% of head and neck cancers being implicated with cannabinoid receptors CB1 and CB2.
- CB2 receptor is not implicated with thyroid cancer but remains at about 50% of head and neck cancers being implicated with CB2 receptors.
- a benefit of an oral mucosal therapeutic is the release of CBD into the oral mucosal tissues, and thus for the potential for direct contact with head and neck cancer tissues.
- application of the CBD can be modified to meet the specific needs of the particular cancer.
- Oral mucosal application will ultimately yield to the salivary glands, and the CBD materials held in the mouth will eventually wash into the GI tract. However, this also allows for tissue accumulation down the esophagus and the rear portions of the mouth and upper throat.
- intravaginal therapy will allow for uptake through the vaginal mucosa and deliver systemic levels of CBD to the body.
- rectal applications are suitable, as rectal administration bypasses the GI tract and has faster rates of action and higher bioavailability.
- rectal administration results in higher systemic circulation of the drug, here, CBD, than oral GI administration.
- HBSS Hank’s Balanced Salt Solution
- P/S Pencillin/Streptomycin
- the filter was removed, and the flow-through with the cells was collected in 5% FBS AD+++ medium (comprising 1% ITS, 2% B27, 1% N2, 25% WRN, hegf-50 ng/mL, hfgf-10-lOOng/mL, Nicotinamide- ImM, N- acetyl cysteine-1.25mM, Primocin-0.2%, Estrogen-2nm, A8301-0.5uM, and Y27632).
- This cell suspension was centrifuged at 1000 rpm for 5 minutes at room temperature to get the cell pellet for counting. Upon checking under hemocytometer cell number was calculated and processed for organoid culture.
- PROTOCOL FOR ALL TESTS PATIENT-DERIVED ORGANOID (PDO) CULTURE AND DRUG TREATMENT
- 2-3xlO A 3 cells were plated in a pre-warmed (37°C) 96-well plate in 10pL of Matrigel (5% FBS AD+++ medium) per well. Individual patient cell organoid was cultured separately in different plates. Individual patient cells were handled separately to reduce the chance of cross-contamination. After mixing cells with Matrigel, lOpl droplets were placed in wells and put in a 37°C incubator with 5% CO2 for 30 minutes.
- the plate Upon solidification of the Matrigel droplet with cells inside, the plate was placed inside a sterile hood and immersed the Matrigel droplet in 200pL of organoid growth media. Cells were allowed to grow into mature organoids for 14 days. Treatment with individual CBD agents (Broad Spectrum, Full Spectrum, CBD Isolates, and CBDA) or in combination with chemotherapeutic agents (Paclitaxel, Doxorubicin or Carboplatin) was started from day 1, where the individual drug or drug combinations were added in the growth medium. All treatments were done in triplicate, including vehicle-only controls (Dimethyl sulfoxide in culture medium at the highest concentration used for drug treatments).
- IC50 specific dose
- chemotherapeutic agents Paclitaxel, Doxorubicin or Carboplatin
- IC50 is the 50% inhibitory concentration which is conventionally used to determine drug potency with cell-based cytotoxicity tests.
- Luminescence was measured on a FLUOstar OPTIMA plate reader (BMG Lab technologies, Offenburg, Germany). Analysis was performed by normalizing treatment values to the vehicle control and plotting them as a percentage of the vehicle control. Drug IC50 values were determined by inhibitor vs normalized response-variable slope using least squares regression in Graphpad Prism 9.
- MOUSE MODEL PATIENT-DERIVED XENOGRAFT (PDX) MOUSE GENERATION
- Tumor size was measured along with body weight at the time of tissue collection. All tumor tissues were removed carefully from the euthanized mouse body. Tumor tissue samples were kept for histology, proteomics, genomics, and other downstream processing. All downstream processing was completed following NCI Patient-Derived Models Repository SOPs. Tumor volume graph will be plotted using GraphPad Prism 9.
- Clinical Dosage (mg/m 2 ) (PDO dosage in mg/culture plate surface area cm 2 ) x 100 2 .
- the Food and Drug Administration has suggested that the extrapolation of animal dose to human dose is correctly performed only through normalization to body surface area (BSA), which often is represented in mg/m 2 .
- the correction factor (Km) is estimated by dividing the average body weight (kg) of species to its body surface area (m 2 ). For example, the average human body weight is 60 kg, and the body surface area is 1.62 m 2 .
- the Km factor for human is calculated by dividing 60 by 1.62, which is 37 and same way the mouse Km factor was calculated, which is 3.
- Dosage for mg/m 2 Km x dosage in mg/kg.
- mice utilized intraperitoneal dosing of various formulations of cannabis extracts comprising a known quantity of CBD.
- Dosing was 30 mg/kg of each of the cannabis extracts, the results of the CBD only study is defined in FIG. 5.
- the concentration of CBD used in each case remains on the low end of the therapeutic dose suitable for administering to a human patient, or to a mouse.
- the low doses were utilized in order to show impact of the cannabis extracts, instead of each of the data going to zero, by using double, triple, or higher of the dose as administered to the mice, all of which would be appropriate human equivalent doses.
- administering higher doses of CBD will yield a greater reduction in tumor volume in the mouse model.
- administering cannabis extracts is effective in greatly slowing the growth of endometrial cancer tumors, and ultimately reduces the tumor size, which may result in the eradication of tumor cells, by administering the cannabis extracts to the mice.
- Cannabis extracts for therapeutic use in the methods herein are generated by an extraction process to remove desired materials from the trichomes and other green material from plants within the cannabis genus.
- a wide variety of cannabinoids have been isolated from the cannabis plant, and some have reported 483 identifiable chemical constituents known to exist in the cannabis plant, many of which are generated in levels that are below the level of quantitation.
- the cannabis extracts utilized herein utilize cannabis strains that having high concentrations of CBD, and the products being generated typically are evaluated based on a CBD content in mg.
- the cannabis extracts further, preferably, comprise certain amounts of array of cannabinoids and other phytonutrients such as essential fatty acids, flavonoids, terpenes and essential vitamins and minerals
- a representative, nonlimiting sample of the cannabis extract of the present disclosure comprises concentrations of certain compounds within the following ranges:
- the formulation has the following fingerprint:
- a simplified approach to the formulations is that the BSHE includes between 60-95% of a CBD, THC of 0%-5%, and additional cannabinoids between 0.1% and 20%. Additional elements include between 0.1% and 20% of waxes and fatty acids.
- the additional cannabinoids comprising the 0.1% and 20% are selected from the group comprising: ⁇ 8 -THC, ⁇ 9 -THCA, CBDA, CBC, CBDV, CBG, CBGA, CBN, and combinations thereof.
- the meaning therefore, includes one or more of these cannabinoids, but does not exclude additional cannabinoids.
- at least one additional cannabinoid is present in the formulation at between 0.1 and 10%, selected from the group consisting of: ⁇ 8 -THC, ⁇ 9 -THCA, CBDA, CBC, CBDV, CBG, CBGA, CBN, and combinations thereof.
- ENDOMETRIAL CANCER PATIENTS' A total of 11 patients (8 patients with grade 1 and 3 patients with grade 2). These patients are aged between 40 to 75 years of age. The tissue samples were collected at time of surgery (total hysterectomy or total hysterectomy bilateral salpingo-oophorectomy) and disease was confirmed by the pathologist. Patients are consecutively and prospectively included when diagnosed with a pelvic mass of suspected uterine origin and are admitted for surgery for a clinically suspicious malignant endometrial growth. To be eligible for enrolment patients are required to be 18 years of age or older and have a diagnosis of endometrial cancer with a planned surgical intervention.
- Menopause status defined as one year of amenorrhea, is checked for women between 47 and 56 years of age. Patients ⁇ 47 years are considered premenopausal and women >56 years, postmenopausal.
- the exclusion criteria are: pregnancy, significant concomitant diseases such as chronic heart failure, severe chronic liver or renal disease, a prior bilateral oophorectomy, pelvic endometriosis or adenomyosis or ovarian primary tumors, and serious medical or psychiatric conditions that may prevent compliance with the protocol. Prior to the collection of biological samples and surgery, all patients are required to give full informed written consent.
- ⁇ 9E4/?Z4JV CANCER PATIENTS A total of 10 patients (4 patients who are ascites recurrent chemoresistant, 1 patient who is solid chemo naive, 5 patients who are solid chemoresistant, all ten patient’s metastatic disease).
- Patients are consecutively and prospectively included when diagnosed with a pelvic mass of suspected ovarian origin and are admitted for surgery for a clinically suspicious malignant pelvic mass of ovarian/tubal origin.
- To be eligible for enrolment patients are required to be 18 years of age or older and have a diagnosis of an ovarian cyst or a pelvic mass with a planned surgical intervention.
- Menopause status defined as one year of amenorrhea, is checked for women between 47 and 56 years of age. Patients ⁇ 47 years are considered premenopausal and women >56 years, postmenopausal.
- the exclusion criteria are: pregnancy, significant concomitant diseases such as chronic heart failure, severe chronic liver or renal disease, a prior bilateral oophorectomy, and serious medical or psychiatric conditions that may prevent compliance with the protocol.
- Prior to collection of biological samples and surgery all patients are required to give full informed written consent. After surgery, the tumors are examined by an experienced gynecology pathologist for diagnosis, histology, grade, and stage (I-IV), according to FIGO standards.
- ENDOMETRIOSIS PATIENTS' A total of 9 patients (2 patients with ovarian endometrioma and 7 patients with deep endometriosis), Patients were those referred by their general practitioners or other clinicians for investigation of pelvic pain or for diagnosis and/or treatment of endometriosis. Those who agreed to undergo laparoscopic surgery for investigation and treatment of endometriosis, pelvic pain or bilateral salpingoophorectomy for strong family history of breast and ovarian cancer were approached and recruited.
- Inclusion criteria were as follows: ‘endometriosis cases’ were defined as women diagnosed with endometriosis at laparoscopy and confirmed histologically; ‘controls with pain’ were defined as symptomatic women with pelvic pain of unknown cause or chronic pelvic inflammatory disease without surgical evidence of endometriosis; ‘controls without pain’ were regularly cycling women with no known disease undergoing bilateral tubal ligation and/or prophylactic bilateral salpingoophorectomy due to familial risk of breast and ovarian cancer and with no visual evidence of endometriosis at laparoscopy.
- the BSHE or FSHE comprise between 50 to 99.9% CBD. Accordingly, a 10 mg dose of BSHE or FSHE comprises between 5 to 9.9 mg of CBD.
- the remaining components of the BSHE or FSHE comprise additional cannabinoids, terpenes, polyphenols, essential fatty acids, and phytonutrients.
- the concentration of CBD is typically between 5 and 50 mg/mL of a pharmaceutical composition.
- Certain compositions comprise additional excipients and ingredients, including but not limited to a fat, an oil, MCT oil, long chain triglyceride oils, very long chain triglyceride oils.
- Terpene components including but not limited to ⁇ -myrcene, ⁇ - caryophyllene, linalool, a pinene, citral, D- Limonene, Eucalyptol.
- Polyphenols may include, but are not limited to catechins, quercetin, cannflavin A/B/C, rutin, and chlorogenic acid.
- Omega 3, omega 6, and omega 9 fatty acids may be present, as well as additional phytonutrients such as tocopherol, sterols, carotene, aliphatic alcohols, and certain minerals.
- These components, including the carrier may make up to 90% by weight of the pharmaceutical composition, however, more preferably CBD comprises between 1 and 90% of the pharmaceutical composition.
- a preferred embodiment is related to a method of treatment of a head and neck cancer comprising, administering to a patient an effective amount of a pharmaceutically acceptable composition comprising CBD, wherein the composition comprises a BSHE or FSHE.
- an effective amount is one effective to generate a concentration of at least 10 ⁇ g/mL of the BSHE or FSHE at the target tissue, and more preferably at least a target concentration of at least 20 ⁇ g/mL.
- an effective dose is between 10 and 4250 mg a day of CBD, wherein said CBD is provided in a BSHE or FSHE through mucosal dosing.
- the methods for treatment herein are effective in eliminating inappropriate lesions, i.e., cells that have migrated from their intended location in the body. Furthermore, these methods stop or retard growth of the squamous cells or parent cells outside of their normal location without exerting unacceptable damage to the parent cells.
- the method of treatment may be to relieve and treat a cancer selected from the group consisting of: squamous cell carcinoma, oral cavity, nasopharynx, oropharynx, larynx, paranasal sinus, sinus, salivary, esophagus, and combinations thereof.
- the method of treatment comprises treating these diseases through application of a pharmaceutically acceptable composition through mucosal administration, selected from one of oral mucosal, nasal mucosa, intravaginal, or rectal administration, said pharmaceutically acceptable composition comprising a CE, and preferably one of a BSHE or FSHE comprising CBD at between 75 and 99% of the total weight of the BSHE or FSHE, or a CBD isolate or CBDA isolate.
- an effective amount is one effective to generate a concentration of at least 10 ⁇ g/mL of CBD at the target tissue.
- an effective dose is between 10 and 4250 mg a day of CBD, wherein said CBD is provided in CE in a pharmaceutically acceptable carrier.
- a combined therapy comprises an oral or oral mucosal therapeutic in addition to the intravaginal or rectal dose.
- a preferred embodiment is a composition that has an acidic pH, preferably between 3.5 and 6, within a carrier suitable for intravaginal application.
- the oral administration it may be suitable to add or coadminister with a high-fat component to increase bioavailability, or to modify the pH or osmolality to increase the rate of absorption or the uptake of the CBD into the oral mucosa.
- the therapeutic treatment of head and neck cancer was treated by reduction of the tumor size and selective destruction of the head and neck cancer cells can be treated through administering a CE comprising CBD.
- the administration is preferably through a mucosal dosing route, such as intravaginally, oromucosally, rectally, or within the nasal passage, or two or more of these dosing routes.
- a dose can be provided once every three days, every second day, every day, daily, or several times a day, such as two, three, four or more times a day.
- the therapeutic dose is preferably between 20 and 4250 mg a day.
- a dose of between 25 and 1250 mg of CBD from a FSHE or BSHE is given at least once a day.
- the FSHE or BSHE is part of a composition comprising a carrier to aid in administering the CE.
- the carrier is a fat or oil as a carrier for mucosal delivery.
- the FSHE or BSHE comprises a fat or oil as a carrier for mucosal application.
- the FSHE or BSHE comprises at least one terpene.
- the FSHE or BSHE comprises a fat or oil as a carrier for intravaginal application, and further comprises at least one terpene.
- the CE preferably comprises CBD from 5O- 99.9% of the weight of the CE.
- the CE preferably further includes at least one additional cannabinoid such as CBC, CBG, CBDA, CBDV, ⁇ 9 -THC, wherein the total concentration of the one additional cannabinoid is between 0.1 and 49%.
- the CE may also comprise at least one of a terpene, a polyphenol, a fatty acid, or a phytonutrient. Each of these are preferably derived from the cannabis plant and present due to the extraction process.
- treatment of head and neck cancer comprises treatment with both a chemotherapeutic agent and also a CE comprising CBD.
- the CE is administered as provided above.
- the chemotherapeutic agent is administered in its normal route of administration.
- the chemotherapeutic agent is preferably administered at a reduced dose as compared to its normal dose. The reduced dose is possible based upon the determined synergy between the chemotherapeutic agent and the CE.
- Administration of the CE may be by any suitable route, however, it is preferred for oromucosal treatment to allow for high bioavailability of the CBD adjacent to the lymph nodes in the mouth and throat, and adjacent to the cancerous tissues, as well as reducing the first pass metabolism through mucosal dosing.
- the CE is preferably a FSHE or a BSHE, wherein the concentration of CBD is preferably at least 50%, and more preferably, at least 60, 65, 70, 75, 80, 85, 90, or 95%, with the remaining portion of the FSHE or the BSHE comprising at least one additional cannabinoid at a concentration of between 0.1 to 40% by weight of the CE.
- the FSHE or the BSHE comprise at least two cannabinoids, each having a concentration of at least 0.1% by weight of the CE.
- the additional cannabinoid is one or more of: CBC, CBG, CBDA, CBDV, or ⁇ 9 -THC.
- chemotherapeutic agent with the CE was effective in reducing the prevalence of endometrial cancer, which had spread throughout the body in the treated patient.
- Administration via intravaginal and oral mucosal administration showed a complete reduction in the size of the cancer cells via the PET scan, and thus will also be effective for treating female patients with head and neck cancer with this administration strategy.
- the treatment is indicated for chemosensitve head and neck cancer.
- CE with CBD alone may be sufficient, or administered jointly with a chemotherapeutic agent.
- the treatment is indicated for metastatic chemosensitive head and neck cancer, wherein the head and neck cancer cells have metastasized and spread beyond the mouth and face.
- the head and neck cancer is a chemoresistant cancer.
- the CE can be administered without the need for an additional carrier.
- the composition may be the CE without any further carrier or excipient.
- preferred embodiments include a composition for treatment of head and neck cancer, wherein the composition comprises a cannabis extract (CE), wherein the CE comprises between 1 and 100% by weight of the composition and all percentages therein.
- the CE comprises between 10 and 90% by weight, or 20 by 90% by weight, and preferably between 40 and 80% by weight of the composition.
- the CE is preferably a BSHE, a FSHE, a CBD isolate, or a CBDA isolate.
- the BSHE, the FSHE, the CBD isolate, or the CBDA isolate make up between 50 and 99.9% by weight of the CE, with the remaining being waxes, fats, fatty acids and the like.
- preferred embodiments utilize a carrier at between 1 and 99% by weight of the composition, and preferably, one or more additional excipients depending on the use case of the composition.
- the composition is typically then administered based upon the dosage in mg of CBD being administered. Wherein the amount of the composition required to meet that mg of CBD depends on the quantity of CBD within each of the CE.
- personalized medicine may play a critical role in providing optimized therapeutic treatments.
- a patient having head and neck cancer may obtain a tissue sample for creation of organoids.
- the tissue sample is typically taken from a biopsy or resected cancerous tissues.
- the organoids can then be grown and tested against a panel of chemotherapeutic agents to identify an optimized treatment plan.
- the preferred plan is to utilize as low a dose of chemotherapeutic agent as possible, in combination with a CE, in order to eradicate the organoids. Thereafter, treatment of the patient with the optimized chemotherapeutic agent and the CE will provide an optimized therapeutic treatment plan.
- chemotherapeutic agents are highly toxic and the ability to reduce the quantity and number of chemotherapy rounds provides a significant improvement to the cancer treatment, as the significant side effects from chemotherapy can be reduced.
- the cannabis extract is a BSHE.
- the BSHE comprises from between 50 and 99% of CBD, and at least one additional cannabinoid.
- the BSHE comprises at least two additional cannabinoids.
- the CE comprises at least three additional cannabinoids.
- the additional cannabinoids are selected from the group consisting of CBC, CBG, CBD A, CBDV, THCV, or ⁇ 9 -THC.
- the cannabis extract is a FSHE, comprising at least 0.1% to 10% ⁇ 9 -THC.
- a FSHE comprises between 50% and 99% CBD, and between 0.1 to 10% of THC.
- the FSHE comprises a total of 51 to 99.9% cannabinoids, with a total of THC, including ⁇ 8 -THC, ⁇ 9 -THC, ⁇ 9 -THC V, THCV, and THCVA comprising 0.1% to 10% by weight of the CE.
- the CE is an isolate of CBD derived from a cannabis extract.
- the CBD isolate seeks to concentrate the CBD, with the CBD being present at between 70 and 99.9% by weight of the CE.
- the isolate of CBD further comprises at least one additional cannabinoid.
- the isolated CBD further comprises CBN, CBDA or both at a concentration of between 0.1 and 10%.
- Cannabis extracts have only recently begun detailed study into therapeutic effects for treatment of disease. Two molecules typically found in cannabis extracts of highest interest are typically cannabidiol (CBD) and A-9-tetrahydrocannabidiol (THC).
- the extracts contain numerous other cannabaniods and to date, scientists have identified at least 144 cannabinoids produced by plants of the genus cannabis, including the hemp plant. Hemp is defined in the US as a cannabis plant with a delta-9-THC content of 0.3% or less by dried weight, so it is a political definition and not a scientific definition. Accordingly, for purposes of this application, “hemp” is defined as a cannabis plant having a delta-9-THC content of 0.3% or less by dried weight.
- the byproducts of hemp plants, including cannabinoids are federally legal as defined in section 7606 of the 2014 Farm Bill and made permanent in the 2018 Farm Bill.
- cannabinoids include Cannabigerol (CBG), Cannabichromene (CBC), cannabidivarin (CBDV), and Cannabinol (CBN).
- Cannabis extracts can be derived from one or more cannabis plant strains as a source material. Notably, while different strains may produce green material with different proportions of desirable compounds, different growing conditions can impact the precise amounts of each compound even for the same strains.
- Cannabis extracts may include isolates of certain compounds, such as isolated CBD, or may include products that contain a wider variety of cannabinoids and other materials, such as those called a Full spectrum hemp extract (FSHE) and Broad spectrum hemp extract (BSHE), each of which may contain an array of cannabinoids and other phytonutrients such as essential fatty acids, flavonoids, terpenes and essential vitamins and minerals.
- FSHE Full spectrum hemp extract
- BSHE Broad spectrum hemp extract
- cannabinoids offer what is known as the 'entourage effect' - a term created by Ralph Mechoulam to describe the inexplicable synergy that manifests when naturally occurring compounds are consumed in tandem. This effect is thought to be the result of multi-pathway activation and signaling from various nutrients in the cannabis extracts.
- a cannabinoid is any one of a diverse class of chemical compounds that influence cannabinoid receptors (CB1 or CB2). These receptors, plus the cannabinoids that activate them, comprise the endocannabinoid system (ECS).
- ECS endocannabinoid system
- cannabinoids There are three primary types of cannabinoids - endocannabinoids, phytocannabinoids, and synthetic cannabinoids.
- Endocannabinoids also known as endogenous cannabinoids are cannabinoids naturally produced within the body.
- Phytocannabinoids are cannabinoids produced within plants.
- Plants that produce cannabinoids include, but are not limited to: kava, rosemary, liverwort, electric daisy, echinacea, cacao, helichrysum, pepper trees, black truffles, cannabis, as well as a strain of yeast (Pichia pastoris). Additionally, certain cannabinoids can be synthesized. Synthetic cannabinoids, however to date, have shown a greater risk of adverse effects and a lower therapeutic potential, a conclusion shared by multiple systematic reviews comparing safety and tolerability of phytocannabinoids versus synthetic cannabinoids.
- ECS endocannabinoid system
- cannabinoid receptors CB1 and CB2
- endogenous cannabinoids endocannabinoids
- Enzymes that break down endocannabinoids FAAH and MAGL
- Cannabinoid receptors found on the surface of cells, are widespread throughout the body and listen to the environment around each cell. They transmit information on current conditions to the cell and thereby jump-start the proper cellular response. Properly functioning cannabinoid receptors have the crucial function of creating homeostasis in the body's cells.
- CB1 and CB2 receptors are the predominant receptors in the ECS.
- CB1 receptors are abundant in the brain and central nervous system, whereas CB2 receptors are sparse in the central nervous system but are common throughout the periphery, primarily on immune cells.
- Cannabinoid receptors are present in almost every organ and organ system throughout the body. They influence activities in the reproductive system, heart, lungs, brain, blood vessels, GI tract, liver, stomach, and more.
- Cannabinoids, found in hemp (phytocannabinoids), such as CBD, may influence a wide array of bodily functions. These phytocannabinoids interact with the cannabinoid receptors and modulate their activity - while at the same time boosting levels of endocannabinoids.
- CBD works with the cannabinoid receptors by inhibiting FAAH (Fatty Acid Amide Hydrolase), an enzyme that breaks down the naturally produced endocannabinoid anandamide, thus prolonging its half-life.
- FAAH Food Acid Amide Hydrolase
- Anandamide is partially responsible for regulating human reproduction, among its other implications within the body.
- Endocannabinoid receptors are abundant in female reproductive organs and the central nervous system. Their signaling and trafficking influence multiple physiological and pathophysiological functions of female reproduction, including folliculogenesis, oocyte maturation, cytoskeleton rearrangement, endometrial cell motility, endometrial migration & proliferation, decidualization, plasticity, and peripheral innervation.
- cannabinoids exert antiproliferative effects on deep infiltrating endometriosis, and increased cannabinoid signaling may reduce proliferation of endometriotic lesions, the etiology of which shares some genetic basis and pathophysiological overlap with ovarian and endometrial cancers.
- Cannabinoids trigger localized vasodilation and relaxation of pathological smooth muscle contraction and/or spasticity.
- Cannabinoid receptors belong to a superfamily of G protein-coupled receptors. They are single polypeptides with seven transmembrane a-helices, and have an extracellular, glycosylated N-terminus and intracellular C-terminus. Both CB1 and CB2 cannabinoid receptors are linked to Gl/0 proteins. In addition to these receptors, endogenous ligands for these receptors capable of mimicking the pharmacological actions of THC have also been discovered. Such ligands were designated endocannabinoids and included anandamide and 2-arachidonoyl glycerol (2 -AG). Anandamide is produced in the brain and peripheral immune tissues such as the spleen.
- CBD does not readily bind to these receptors and hence has no psychotropic activity. Instead, cannabidiol indirectly stimulates endogenous cannabinoid signaling by suppressing the enzyme that breaks down anandamide (fatty acid amide hydroxylase, “FAAH”). CBD also stimulates the release of 2-AG. Therefore, the mechanisms of action for CBD are complex, varied, and still only partially understood.
- CBD is an antagonist and a partial allosteric modulator of CB1 receptors. There is evidence that CBD stimulates 5HT1A/2A/3A serotonin receptors, TRPV1-2 vanilloid receptors, and glycine channels. CBD does not bind to either CB1 or CB2 receptors and thus most, if not all, of CBDs mechanisms are not directly CB receptor mediated.
- CBD may be implicated in signaling pathways in the body.
- CBD may play a modulatory role with regard to cytokines.
- Cytokines are signaling proteins synthesized and secreted by immune cells upon stimulation. Accordingly, one of the possible mechanisms of immune control by CBD is by perturbing the balance between cytokines produced by T helper subsets, T h 1 and T h 2. In certain prior studies, both anti-inflammatory and proinflammatory effects were shown.
- IL-6 suppression can decrease tissue injury.
- CBD is also known to stimulate vanilloid pain receptors (TRPV-1 receptor), which are known to mediate pain perception, inflammation, and body temperature. CBD may also impact certain adenosine receptors, which play a significant role in cardiovascular function and broadly impact anti-inflammatory effects throughout the body as well as regulate and decrease anxiety and depression and increase the sense of well-being.
- TRPV-1 receptor vanilloid pain receptors
- phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohol, and nonpolar organic solvents, and can also be suspended in emulsions. These natural cannabinoids are concentrated in a viscous resin that is produced in glandular structures known as trichomes within hemp plants. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the plants in the cannabis family. These materials are also present in additional tissues of the plant, most notably in the flowers and leaves of the plants.
- Cannabis extracts for therapeutic use in the methods herein are generated by an extraction process to remove desired materials from the trichomes and other green material from the hemp plant.
- the extraction process at a wide variety of cannabinoids have been isolated from the hemp plant, and some have reported 483 identifiable chemical constituents known to exist in the hemp plant, many of which are generated in levels that are below the level of quantitation.
- the cannabis extracts utilized herein utilize cannabis strains that having high concentrations of CBD, and the products being generated typically are evaluated based on a CBD content in mg.
- the cannabis extracts further, preferably, comprise certain amounts of array of cannabinoids and other phytonutrients such as essential fatty acids, flavonoids, terpenes and essential vitamins and minerals
- THC and CBD are both highly lipophilic and have poor oral bioavailability when swallowed, at between 6 to 10 percent, amounts which may be increased through specific preparations.
- Oral THC formulations exhibit variable absorption and undergo extensive hepatic first-pass metabolism, resulting in lower peak plasma THC concentration relative to inhalation and a longer onset ( ⁇ 120 min) to reach peak concentration.
- CBD a similar plasma concentration-time profile to that of oral THC has been observed. Based on this profile, oral formulations may be useful for patients requiring symptomatic relief over a longer period, though higher concentrations may be necessary, in order to reach therapeutic plasma concentrations, as compared to alternative deliver ⁇ - methods, such as inhalation.
- certain liver toxicities may exist because of the extensive first pass metabolism when higher dosage amounts are needed for therapeutic levels,
- Oral mucosal preparations undergo rapid absorption via the oral mucosa (and hence are useful for symptoms requiring rapid relief), producing plasma drug concentrations higher relative to oral delivery, but reduced relative to inhaled (smoke) consumption of cannabis material.
- part of the dose will be swallowed and thus ingested via the stomach, thus a portion becoming a standard oral formulation.
- Cannabinoids rapidly distribute into well -vascularized organs (e.g., lung, heart, brain, liver), with subsequent equilibration into less vascularized tissue. Distribution may be affected by body size and composition, and disease states influencing the permeability of blood-tissue barriers. Therefore, when targeting less vascularized organs, the distribution and uptake may be reduced, as compared to other organs. This again points to implications for localized administration for EC treatment, instead of simply through the stomach or oral mucosa as with typical applications of therapeutic treatments.
- CBD is hepatically metabolized, primarily by isozymes CYP450, CYP2C19 and CYP3A4 and additionally, CYP1A1, CYP1A2, CYP2C9 and CYP2D6. After hydroxylation to 7-hydroxy cannabidiol (7-OH-CBD), there is further hepatic metabolism and subsequent fecal, and, to a lesser extent, urinary, excretion of those metabolites. CBD, like THC, has also been reported to have a long terminal elimination half-life, with the average half-life following intravenous dosing observed to be 24 ⁇ 6 hours and post -inhalation to be 31 ⁇ 4 hours.
- Dose-response and drug-drug interaction information is lacking. Potential exists for pharmacokinetic interactions between both THC and CBD and other drugs, via inhibition or induction of enzymes or transporters and additionally, pharmacodynamic drag-drug interactions. There is a potential for CBD to compete with drugs metabolized through CYP 450 pathways, specifically those that interact with enzymes CYP3A4, CYP2C19, and CYP2D6. Dose adjustments may be necessary with substrates of CYP2C8, CYP2C9, CYP2C19, CYP1A2 and CYP2B6. Current literature demonstrates clinically significant drug interactions at doses of 20mg/kg/day. One published case study concluded meaningful interactions with Warfarin at a dose of lOmg/kg.
- CBD significantly inhibits P -glycoprotein-mediated drug transport, suggesting that CBD could potentially influence the absorption and disposition of other coadministered drugs.
- CBD was observed to be a potent inhibitor of CYP2C19 enzymes.
- THC is a partial agonist of CB 1 receptors, the mechanism by which intoxication and psychotropic effects of cannabis can occur.
- CBD does not bind with CB1 receptors, THC elicited anxiety, dysphoria, sedation, psychotic symptoms, subjective intoxication, and increased heart rate, while CBD demonstrated zero adverse effects in controlled studies of the molecules.
- CBD does not possess the risk of intoxication, dependency or withdrawal associated with THC.
- CBD is a potent antagonist and allosteric modulator of CB1 receptors, therefore inhibiting some of the intoxicating and other adverse effects of THC when coadministered.
- coadministration of CBD has been reported to reduce THC-associated adverse psychotropic and cardiovascular effects (tachycardia).
- CBD has been reportedly associated with fatigue and somnolence, potentially compounded by coadmini strati on with CNS-active medications.
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Non-Patent Citations (2)
Title |
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GO YOON YOUNG ET AL: "Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma", SCIENTIFIC REPORTS, vol. 10, no. 1, 26 November 2020 (2020-11-26), pages 1 - 11, XP093011377, Retrieved from the Internet <URL:https://www.nature.com/articles/s41598-020-77674-y.pdf> DOI: 10.1038/s41598-020-77674-y * |
JULIAN KENYON ET AL: "Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol", ANTICANCER RESEARCH, vol. 38, no. 10, 1 October 2018 (2018-10-01), GR, pages 5831 - 5835, XP055685351, ISSN: 0250-7005, DOI: 10.21873/anticanres.12924 * |
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US20230130065A1 (en) | 2023-04-27 |
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